Greasing Interferon's Gears May Pave Way To Greater Therapeutic Benefits, Fewer Side Effects

"Essentially, we found a way to grease the gears that drive theinterferon signal," says Michael J. Holtzman, M.D., the Selma andHerman Seldin Professor of Medicine and director of the Division ofPulmonary and Critical Care Medicine.

The researchers modified the structure of a protein calledStat1, which relays signals from interferon at the cell surface togenes in the cell nucleus. The modification up shifted Stat1's responseto interferon.

The study will appear in the October 7, 2005 issue of theJournal of Biological Chemistry and was selected as the journal's Paperof the Week, which recognizes the top one percent of the journal'spapers in significance and overall importance.

The development of a mechanism to tweak Stat1's responsivenessmay prove particularly useful for patients with such disorders ashepatitis C, multiple sclerosis and many types of systemic cancer, whocurrently benefit from interferon treatment, but sometimes find itdifficult to tolerate the side effects of the high doses required.

"We reasoned that if we could enhance the way interferonproduces its beneficial defensive effects, the body could respond toits normal level of interferon and receive enhanced benefit withoutside effects," Holtzman says.

The group engineered a mutant Stat1 protein in which theidentities of two amino acids were switched. Investigations conductedon cells growing in culture showed that the altered Stat1 proteinsreacted more efficiently to the presence of both type I and type IIinterferons. Further tests revealed that the souped-up Stat1 recruitedmore of a specific protein it needs to pass on the interferon signal,essentially raising the speed limit on signal transmission.

"Ordinarily, the interferon signaling system's rate may beslowed because this helper protein interacts with Stat1 at less thanthe maximum amount," Holtzman says. "It's possible that the maximalsetting would be harmful in the long term, because too much interferoncould lead to inflammatory diseases. But we may find advantages toincreasing Stat1 action in the short term using drug treatments."

Such therapies could allow physicians to turn up the effect ofinterferon temporarily to treat infections or other disorders and thento turn it back down to normal levels when the patient is cured.

"The potential for this 'rheo-Stat' strategy is exciting,"Holtzman says. "As an example, one could improve Stat1 efficiencyduring the winter months in patients at risk of developing seriousviral infections, including children with asthma, heart disease orcompromised immune systems."

It may be possible, as well, to screen patients for levels ofStat1 responsiveness and use the same treatment strategy to correct lowlevels of response, according to Holtzman. The researchers arecurrently screening newborn infants for levels of Stat1 action andtracking their susceptibility to viral infection.

In addition, the group is studying transgenic mice engineeredto carry the same Stat1 mutations that were examined in cells. In thisway, the researchers can investigate the benefits of hyper-responsiveStat1 for infection control and cancer treatment in a living organism.These studies lay the foundation for the development of humantreatments that use drugs that increase Stat1 responsiveness andconsequently enhance the benefits of interferon produced naturally inthe body or given as treatment.

Zhang Y, Takami K, Lo MS, Huang G, Yu Q, Roswit WT, Holtzman MJ.Modification of the Stat1 SH2 domain broadly improves interferonefficacy in proportion to p300/CREB-binding protein coactivatorrecruitment. Journal of Biological Chemistry, October 7, 2005.

Funding from the National Institutes of Health, the MartinSchaeffer Fund and the Alan A. and Edith L. Wolff Charitable trustsupported this research.